tbuckley/cabot-search huggingface dataset:
The Human Acellular Vessel for Vascular Reconstruction or Bypass
Authors: Alexis L. Lauria, Indrani Sen, Todd E. Rasmussen
Journal: JAMA Surgery (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
P469: CHEMORESISTANCE IN ACUTE MYELOID LEUKEMIA: A SINGLE-CELL RNA SEQUENCING APPROACH
Authors: C.-L. Teng, P.-L. Cheng, T.-H. Hsiao, C.-H. Chen
Journal: HemaSphere (2022)

Background: Our previous study demonstrated that myc, mitochondrial oxidative phosphorylation, mTOR, and stemness were independently responsible for chemoresistance in AML. Aims: The current study aimed to further identify the potential mechanisms of chemoresistance of the “7 + 3” induction in AML using a single-cell RNA sequencing (scRNA-seq) approach. Methods: Thirteen untreated de novo AML patients were enrolled and stratified into the complete remission (CR) (n=8) and the non-CR (n=5) groups. We used scRNA-seq to analyze the genetic profiles of 28950 AML cells from these 13 patients. A previously published bulk RNA-seq dataset validated our results. Results: Chemoresistant AML cells had more premature accumulation in early hematopoiesis. The hematopoietic stem cell-like cells from the non-CR group expressed more leukemic stem cell markers (CD9, CD82, IL3RA and, IL1RAP) than those from the CR group. Besides, chemoresistant progenitor cells had impaired myeloid differentiation due to early hematopoiesis arrest. Importantly, the AML cells analyzed by the scRNA-seq and bulk RNA-seq harbored comparable myeloid lineage cell fraction, which internally validated our results. Using the TCGA database, our analysis demonstrated that AML patients with a higher expression of chemoresistant genetic markers (IL3RA and IL1RAP) had a worse overall survival (p < 0.01 for IL3RA; p < 0.05 for IL1RAP). Image:Summary/Conclusion: The AML cells responsive and resistant to the “7 + 3” induction had diverse cell origins according to specific genetic biomarkers using a scRNA-seq approach. Besides, hematopoiesis arrest occurred earlier in chemoresistant AML cells. This result provided an insight into a more understanding of chemoresistance in AML.
DLGAP1-AS2–Mediated Phosphatidic Acid Synthesis Activates YAP Signaling and Confers Chemoresistance in Squamous Cell Carcinoma
Authors: Yabing Nan, Qingyu Luo, Xiaowei Wu, Shi Liu, Pengfei Zhao, Wan Chang, Aiping Zhou, Zhihua Liu
Journal: Cancer Research (2022)

Abstract Squamous cell carcinomas (SCC) constitute a group of human malignancies that originate from the squamous epithelium. Most patients with SCC experience treatment failure and relapse and have a poor prognosis due to de novo and acquired resistance to first-line chemotherapeutic agents. To identify chemoresistance mechanisms and to explore novel targets for chemosensitization, we performed whole-transcriptome sequencing of paired resistant and parental SCC cells. We identified DLGAP1 antisense RNA 2 (D-AS2) as a crucial noncoding RNA that contributes to chemoresistance in SCC. Mechanistically, D-AS2 affected chromatin accessibility around the histone mark H3K27ac of FAM3 metabolism regulating signaling molecule D (FAM3D), reducing FAM3D mRNA transcription and extracellular protein secretion. FAM3D interacted with the Gαi-coupled G protein–coupled receptors formyl peptide receptor 1 (FPR1) and FPR2 to suppress phospholipase D (PLD) activity, and reduced FAM3D increased PLD signaling. Moreover, activated PLD promoted phosphatidic acid (PA) production and subsequent nuclear translocation of yes-associated protein (YAP). Accordingly, in vivo administration of a D-AS2–targeting antisense oligonucleotide sensitized SCC to cisplatin treatment. In summary, this study shows that D-AS2/FAM3D-mediated PLD/PA lipid signaling is essential for SCC chemoresistance, suggesting D-AS2 can be targeted to sensitize SCC to cytotoxic chemotherapeutic agents. Significance: This study identifies D-AS2 as a targetable lipid-related long noncoding RNA that increases phospholipase D activity to promote YAP signaling, triggering chemoresistance in SCC.
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Journal: JAMA Network Open (2022)

Huiyu Deng, PhD; Zahra Eftekhari, MS; Cameron Carlin, MS; Jula Veerapong, MD; Keith F. Fournier, MD; Fabian M. Johnston, MD, MHS; Sean P. Dineen, MD; Benjamin D. Powers, MD, MS; Ryan Hendrix, MD; Laura A. Lambert, MD; Daniel E. Abbott, MD; Kara Vande Walle, MD; Travis E. Grotz, MD; Sameer H. Patel, MD; Callisia N. Clarke, MD; Charles A. Staley, MD; Sherif Abdel-Misih, MD; Jordan M. Cloyd, MD; Byrne Lee, MD; Yuman Fong, MD; Mustafa Raoof, MD
Prophylactic Antibiotic Regimens in Tumor Resection Surgery Involving a Prosthesis—Reply
Authors: Michelle Ghert, Patricia Schneider, Timothy O’Shea
Journal: JAMA Oncology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
P763: VENETOCLAX WITH AZACITIDINE IN RELAPSE/REFRACTORY HIGHER RISK MYELODYSPLASTIC SYNDROME: UPDATED PHASE 1 RESULTS
Authors: S. P. Desikan, G. Montalban-Bravo, M. Ohanian, N. Daver, T. Kadia, S. Venugopal, K. Chien, H. Kantarjian, G. Garcia-Manero
Journal: HemaSphere (2022)

Background: Patients with higher risk (HR) MDS status post HMA failure have poor survival, 4-6 months. [Lancet Oncology Apr 2016] The combination of azacitidine(Aza) and venetoclax(Ven) has produced encouraging results in the frontline settings for patients with HR disease.(Garcia et.al ASH 2019) Aims: The primary objective is to establish the safety of azacitidine and venetoclax in HR MDS after HMA failure. The secondary objectives include rates of CR, marrow response, transfusion independence, duration of response, and overall survival. Methods: In this phase 1 study, patients 18 years and older with HMA failure (relapse or progression after 4 cycles), adequate organ function and performance status are being enrolled. Patients who had received prior Ven were excluded. All patients received Aza 75mg/m2 on D1-5. A 3 + 3 design was utilized with Ven. A 3 + 3 design was utilized with Ven with dose levels 0, 1, 2 receiving 100mg, 200mg, and 400mg respectively. Patients are currently being enrolled in the expansion cohort(400mg). Response was determined based on IWG06 criteria. Results: Baseline characteristics are in Table 1. Fifteen patients have been enrolled with a median age of 78[67 – 81]. The median blast% on enrollment was 9%[6 – 17] with a median ANC, Hgb, and PLT of 1.67 K/µL, 7.7mg/dL, and 39 K/µL. When stratified based on cytogenetics, 1 (7%) had good risk, 7 (47%) patients had intermediate risk, 2 (13%) had poor risk, and 5(33%) had very poor risk. When stratified based on IPSS-R criteria: 2(13%) had intermediate risk, 5(33%) had high risk, and 8(54%) had very high risk disease. ASXL1 and TP53 mutations were enriched, occurring in 46% and 53% of patients. Four(33%) patients had Grade ¾ cytopenias (either thrombocytopenia or neutropenia) relating to this combination. Three patients required dose reductions. No tumor lysis syndrome has occurred to date. Two patients recently started treatment and could not be included for response assessment. Among the 13 patients evaluable, the ORR is 62%(n=8). The median number of cycles to response was 1[1-4]. Responses consisted of 1 CR, 4 marrow responses with either platelet or neutrophil recovery, and 3 marrow responses without count recovery. Three patients achieved transfusion independence. Five patients had NR with 4 having TP53 mutations. The median OS was 8.5 months with a 30 day and 60 day mortality of 8% and 23% respectively. Early mortality was related to infection in 2 patients and progression in another. Image:Summary/Conclusion: With a response rate of 62% and an OS of 8.5 months, this combination may have benefit in HR RR MDS. TP53 mutations and higher cytogenetic risk confer poor prognosis.
Gut microbiota and metabolites associate with outcomes of immune checkpoint inhibitor–treated unresectable hepatocellular carcinoma
Authors: Pei-Chang Lee, Chi-Jung Wu, Ya-Wen Hung, Chieh Ju Lee, Chen-Ta Chi, I-Cheng Lee, Kuo Yu-Lun, Shih-Hsuan Chou, Jiing-Chyuan Luo, Ming-Chih Hou, Yi-Hsiang Huang
Journal: Journal for ImmunoTherapy of Cancer (2022)

Background Immune checkpoint inhibitors (ICIs) are promising agents for unresectable hepatocellular carcinoma (uHCC), but lack effective biomarker to predict outcomes. The gut microbiome can modulate tumor response to immunotherapy, but its effect on HCC remains unclear. Methods From May 2018 to February 2020, patients receiving ICI treatment for uHCC were prospectively enrolled; their fecal samples were collected before treatment. The fecal microbiota and metabolites were analyzed from 20 patients with radiology-proven objective responses (OR) and 21 randomly selected patients with progressive disease (PD). After March 2020, 33 consecutive Child-Pugh-A patients were recruited as a validation cohort. Additionally, feces from 17 healthy volunteers were collected for comparison of background microbes. Results A significant dissimilarity was observed in fecal bacteria between patients with OR and patients with PD before immunotherapy. Prevotella 9 was enriched in patients with PD, whereas Lachnoclostridium, Lachnospiraceae, and Veillonella were predominant in patients with OR. Ursodeoxycholic acid and ursocholic acid were significantly enriched in the feces of patients with OR and strongly correlated with the abundance of Lachnoclostridium . The coexistence of Lachnoclostridium enrichment and Prevotella 9 depletion significantly predicted better overall survival (OS). In the validation cohort, better progression-free survival (PFS) and OS were noted in patients who had a preferable microbial signature in comparison with counter-group (PFS: 8.8 months vs 1.8 months; OS: not reached vs 6.5 months, both p&lt;0.001). Conclusions Fecal microbiota and bile acids were associated with outcomes of immunotherapy for uHCC. These findings highlight the potential role of gut microbiota and metabolites as biomarkers to predict outcomes of ICI-treated HCC.
P384: THE ROLE OF THE MANNOSE RECEPTOR C-TYPE 2 (MRC2) IN LEUKEMIC STEM CELL MAINTENANCE IN AML
Authors: M. Arnone, E. Görsch, S. Pöschel, P. Godavarthy, A. Stanger, S. Rudat, C. Lengerke
Journal: HemaSphere (2022)

Background: Therapy-resistant leukemia-initiating cells, so called leukemic stem cells (LSC), are responsible for disease relapse and a major cause of death in patients with acute myeloid leukemia (AML). Effective identification and targeting of LSCs are thus important goals. Our previous RNA sequencing analyses revealed that the MRC2 gene, which encodes a transmembrane receptor known for its ability to bind and degrade collagen as well as for its pro-migratory and -invasion functions, is enriched in LSCs. Aims: We aim to gain a better understanding of the function(s) of MRC2 in AML in general and LSCs in particular. Methods: We used flow cytometry to characterize MRC2 expression in primary AML samples and healthy cells from the hematopoietic system. Imaging flow cytometry experiments were performed to study the role of MRC2 in gelatin uptake. Results: We found that mRNA expression of the MRC2 gene was increased in the LSC compartment of 5 AML patients compared to their non-LSC counterparts. Analyzing MRC2 cell surface presentation by flow cytometry, we found that AML cell lines (n=10) displayed the highest levels of MRC2 expression followed by healthy CD34+ cord blood (CB) cells (n=7), while primary AML patient samples (n=21) were characterized by an intermediary MRC2 cell surface presentation with the lowest levels of MRC2 presentation in differentiated healthy hematopoietic cells. Interestingly, high MRC2 expression correlated with increased clonogenic activity as only sorted MRC2+ but not MRC2- primary AML cells from the same sample were able to form colonies in a methylcellulose assay; and siRNA-mediated knockdown of MRC2 in the bulk of primary AML cells led to a reduction in colony formation when compared to control siRNA transfected cells. Furthermore, using CRISPR/Cas9 we generated a MRC2 knock-out AML cell line and observed in in vitro assays that MRC2 expression is required for migration, invasion and adhesion to collagen and laminin 421. Finally, we could show by imaging flow cytometry (ImageStream) that AML cells lacking MRC2 expression were unable to internalize fluorescently-labelled gelatin. Summary/Conclusion: Together, our results suggest that AML cells benefit from MRC2 expression due to its multiple functions involving migration, invasion and the interaction with extracellular matrix components. Additionally, MRC2 has a potential role in LSC biology such as the maintenance of stemness-associated properties. Further in vivo studies will improve our understanding of MRC2, which could then inform us on novel therapeutic approaches.
S273: EVIDENCE OF NONINFERIORITY OF MITAPIVAT VERSUS SPLENECTOMY IN MURINE HEREDITARY SPHEROCYTOSIS
Authors: A. Matte’, A. Recchiuti, E. Federti, P. A. Kosinski, V. Riccardi, I. Iatcenko, L. Dang, A. Iolascon, R. Russo, C. Brugnara, A. Janin, C. Leboeuf, N. Mohandas, L. De Franceschi
Journal: HemaSphere (2022)

Background: Hereditary spherocytosis (HS) is the most common cause of inherited red cell membranopathy, due to mutations in genes encoding membrane or cytoskeletal proteins, including band 3, ankyrin, spectrin or band 4.2. Loss of membrane cohesion results in surface area loss and generation of spherocytic red cells with decreased cellular deformability and reduced red cell survival due to splenic sequestration. Relative PK deficiency has been observed in HS red cells (Andreas O et al. BJH 187: 386, 2019). Splenectomy is the gold standard treatment of anemia in patients with HS. However, the benefits of splenectomy in mild HS is still controversial and its cost/effectiveness might be underestimated. Using band 4.2-/- mice, a well-established model of HS (Peters LL et al JCI 103: 1527, 1999), we recently show that mitapivat, an oral PK activator, ameliorates anemia, reduces chronic hemolysis and improves RBC features in 4.2-/- mice (Matte A et al. EHA 2021). Aims: To understand whether the oral pyruvate kinase activator, mitapivat, is not less efficacious than splenectomy in treatment of anemia in 4.2-/- mice. Methods: Splenectomized 4.2-/- mice (2.5 months of age) were either treated with vehicle or mitapivat at dosages of 100 mg/kg/day over 4 months. An unsplenectomized group of 4.2-/- mice treated with and without mitapivat was also analyzed. The following parameters were evaluated: hematologic parameters, markers of hemolysis, erythropoiesis and iron homeostasis. Results: In band 4.2-/- mice, splenectomy resulted in (i) amelioration of anemia with reduced reticulocyte count (Hb 13.3 ±0.5 g/dL, n=3 vs 11.9±0.6 g/dL, n=8; P<0.05; retics: 4.9±0.5%, n=3 vs 10.0±1.4%, n=8 P<0.05) and reduced hemolytic indices (LDH, total bilirubin) when compared to non-splenectomized 4.2-/- mice. The decreased hemolysis was associated with reduction in serum erythropoietin (EPO). Mitapivat was non-inferior to splenectomy for amelioration of anemia (Hb 13.4±0.8 g/dL, n=11 vs 11.9±0.6 g/dL, n=8), reduction in reticulocyte count (retics: 7.8±1.4%, n=11 vs 10.0±1.4%, n=8 P<0.05) and EPO levels (401±123 U/L, n=3). Noteworthy, in splenectomized 4.2-/- mice, mitapivat further improved Hb (Hb: 14.1±0.3 g/dL, n=3), reduced reticulocyte counts (retics: 3.6±0.2%, n=3) and EPO levels when compared to vehicle treated splenectomized 4.2-/- mice. Image:Summary/Conclusion: Our data indicate that mitapivat was at least as effective as splenectomy in treatment of anemia in a murine model of HS.
P578: GILTERITINIB FOR RELAPSED/REFRACTORY FLT3 MUTATED ACUTE MYELOID LEUKEMIA A REAL-WORLD, MULTI-CENTER, MATCHED ANALYSIS
Authors: S. Shimony, J. Canaani, E. Kugler, B. Nachmias, R. Ram, A. Frisch, C. Ganzel, V. Vainstein, Y. Moshe, S. Aumann, M. Yeshurun, Y. Ofran, P. Raanani, O. Wolach
Journal: HemaSphere (2022)

Background: Patients with FLT3-mutated relapsed or refractory (R/R) acute myeloid leukemia (AML) have a dismal prognosis. Gilteritinib is a FLT3 tyrosine kinase inhibitor (TKI) recently approved for patients with R/R AML. Aims: We aimed to characterize real-world data regarding gilteritinib treatment in FLT3-mutated R/R AML and to compare outcomes with matched FLT3-mutated R/R AML patients treated with chemotherapy-based salvage regimens. Methods: Survival analysis was performed by Kaplan Meyer with log rank test to compare between subgroups. Cox proportional hazards regression models were fitted to predict effect of covariates on overall survival (OS) and event free survival (EFS). All statistical analyses used 2-sided p value with a threshold of 0.05. Results: Twenty-five patients from six academic centers were treated with gilteritinib for FLT3-mutated R/R AML. The median age was 58 (IQR1-3 47-73) years, 80% (n=20) were treated with a prior intensive induction regimen and 40% of them received prior TKI therapy. After a median time of seven months post gilteritinib initiation (range 1-34), 12 patients (48%) achieved complete response (CR) with gilteritinib (figure 1A). The estimated median overall survival (OS) of the entire cohort was eight (CI 95% 0-16.2) months and was significantly higher in patients who achieved CR compared to those who did not (16.3 months, CI 95% 0-36.2 vs. 2.6 months, CI 95% 1.47-3.7; p value=0.046, figure 1B). In a multivariate cox regression analysis, achievement of CR was the only predictor for longer OS (HR 0.33 95% CI 0.11-0.97, p=0.044). Prior TKI exposure did not affect OS but was associated with better event-free survival (HR 0.15 95% CI 0.03-0.71, p=0.016). An age and ELN-risk matched comparison between patients treated with gilteritinib and intensive salvage revealed similar response rates (50% in both groups); median OS was 9.6 months (CI 95% 2.3-16,8) vs. 7 months (CI 95% 5.1-8.9) in gilteritinib and matched controls, respectively (p = 0.869, figure 1C). Image:Summary/Conclusion: In the real-world setting gilteritinib is effective, including in heavily pre-treated, TKI exposed patients.
P444: IDENTIFICATION OF FUNCTIONAL GENETIC DEPENDENCIES IN CEBPA-MUTATED ACUTE MYELOID LEUKEMIA
Authors: L. Proietti, E. Heyes, T. Eder, T. Brandstoetter, G. Manhart, V. Sexl, F. Grebien
Journal: HemaSphere (2022)

Background: C/EBPα is a key myeloid transcription factor that regulates the switch between proliferating uncommitted cells and terminally differentiated cells. The CEBPA gene is mutated in 10-15% of AML patients. CEBPA lesions are divided into C-terminal mutations that abrogate DNA binding and N-terminal frameshift mutations, which cause expression of an N-terminally truncated isoform, termed p30. A large fraction of AML patients carries biallelic CEBPA mutations. In these patients, the shorter C/EBPα p30 variant is the only functional isoform of C/EBPα. While we and others have identified molecular mechanisms underlying the development and maintenance of CEBPA-mutated AML, a comprehensive analysis of vulnerabilities that is associated with this disease subtype is lacking. Aims: We aimed to characterize the functional genetic dependencies of AML with biallelic CEBPA mutations. Methods: We generated an immortalized AML cell line by serial transplantation of fetal liver cells carrying biallelic CEBPA mutations (CNC, CebpaN-terminal/C-terminal) followed by prolonged culture of leukemic cells. After stable expression of Cas9, we performed a genome-scale CRISPR/Cas9 loss-of-function screen in CNC cells and compared the results to genome-wide screening results from the HPC7 hematopoietic multipotent progenitor cell line, which were used as a representative of the healthy, untransformed state. Results: Transplantation of CNC cells into C57BL/6 mice induced an aggressive Mac1+/Gr1+/c-Kit+ leukemia within 7 weeks, similar to the initial model (Bereshchenko et al, 2009). This immuno-phenotype was preserved upon prolonged in vitro culture. Analysis of the CRISPR/Cas9 screen in CNC cells identified 2488 genes whose mutational inactivation was associated with reduced fitness - 438 of these genes are “core” essential, as they have been annotated to be required for the survival of both cancer and normal cells. In HPC7 cells, the loss of 1674 genes caused cell depletion, including 388 core essential genes. Intersection of screening results from CNC and HPC7 cells revealed 1290 commonly depleted genes, of which 380 were core essential. We identified 308 genes that were exclusively required for the proliferation and survival of CNC cells. This list of high-confidence candidates is enriched for genes involved in mRNA metabolism, DNA repair and signaling pathways. We are currently in the process of validating prioritized target genes using a variety of approaches. Summary/Conclusion: This approach allows the acquisition of deeper insights into the molecular mechanisms underlying the development and maintenance of leukemia with CEBPA mutations. Multi-layered validation of high confidence candidates will be performed in vivo and in vitro to identify leukemia-specific vulnerabilities that can serve as starting points for rational targeting strategies.